# Translational studies for identifying and targeting novel pathways in systemic sclerosis pathogenesis

> **NIH NIH P50** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2021 · $69,372

## Abstract

The overall goal of this Center of Research Translation is to utilize biomarker tools and other translational
research observations to discover new therapies for patients with systemic sclerosis (SSc). This goal can be
broken down into four intermediate objectives: understanding pathogenic pathways through translational
studies, developing biomarkers for SSc, developing novel therapeutics, and applying bioinformatic and
systems biology approaches to interpret translational and biomarker data. Among current obstacles to
progress in finding new drugs for SSc patients is the continuing limited understanding of pathogenesis of SSc
disease, in part due to its complexity and heterogeneity, and in part due to the lack of good animal models.
Innovative protocols of University of Pittsburgh Medical Center and Boston University Medical Center for
obtaining SSc skin and lung biosamples will allow investigators to discover the genes, regulatory proteins,
mediators and cells that promote fibrosis and vascular injury in SSc patients. These include very large,
longitudinal clinical-biological sample repositories; SSc lung transplant and warm autopsy programs; and skin
biopsy, ex vivo lung perfusion, functional distal pulmonary arterial myography and lung explant culture
protocols. In Project 1 investigators will validate biomarkers of SSc skin and lung disease, investigate
mesenchymal cell heterogeneity in normal and SSc skin using single cell RNA-seq, and study the effect of
blocking genes associated with myofibroblast differentiation. In Project 2 investigators will examine altered
markers of oxidative stress and mitophagy in SSc leukocytes and pulmonary vascular endothelial cells
obtained during right heart catheterization and from dissected pulmonary arteries of patients with SSc-
associated pulmonary arterial hypertension. They will also investigate the effect of the recently approved Nrf2
inhibitor, dimethyl fumarate, on endothelial cells in these systems. In Project 3 investigators will study
expression of ubiquitin ligases in SSc-associated interstitial lung disease (SSc-ILD). They will also design
optimal ubiquitin ligase antagonists for SSc-ILD using quantitative structure-activity relationships, and test
these inhibitors in lung explant and ex vivo lung perfusion models. Project aims will be supported by three
resource cores: a Clinical and Biological Specimen Core, a Lung Tissue Core and a Translational Genomics
and Data Integration Core. The latter will synthesize data from each project and across projects, to develop
models for common molecular pathways associated with different disease manifestations. The focus of each
of the projects on different SSc clinical manifestations, mediators of disease, and drug inhibitors will provide a
rich, highly collaborative environment for fundamental discovery within bridging project topics and core
resources. This will be further enhanced by the complementary experience of the project and core
investigators in...

## Key facts

- **NIH application ID:** 10476752
- **Project number:** 3P50AR060780-10S1
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** ROBERT A. LAFYATIS
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $69,372
- **Award type:** 3
- **Project period:** 2011-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10476752

## Citation

> US National Institutes of Health, RePORTER application 10476752, Translational studies for identifying and targeting novel pathways in systemic sclerosis pathogenesis (3P50AR060780-10S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10476752. Licensed CC0.

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